The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination

• Published in: Nature communications Vol. 14; no. 1; p. 8248
• Main Authors: McGregor, Lindsay, Acajjaoui, Samira, Desfosses, Ambroise, Saïdi, Melissa, Bacia-Verloop, Maria, Schwarz, Jennifer J., Juyoux, Pauline, von Velsen, Jill, Bowler, Matthew W., McCarthy, Andrew A., Kandiah, Eaazhisai, Gutsche, Irina, Soler-Lopez, Montserrat
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 101/58; 45/70; 631/337/458/1733; 631/378; 631/535/1258/1259; 82/16; 82/83; Alzheimer Disease; Alzheimer's disease; Amyloid beta-Peptides; Assembly; Binding; Biochemistry, Molecular Biology; Bioenergetics; Complex formation; Electron transport chain; Electron Transport Complex I; Energy Metabolism; Enzymes; Humanities and Social Sciences; Humans; Life Sciences; multidisciplinary; NADH-ubiquinone oxidoreductase; Neurodegenerative diseases; Oxidation; Oxidation-Reduction; Pathogenesis; Phosphorylation; Science; Science (multidisciplinary); Structural Biology; Toxicity; β-Amyloid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43865-0

The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer’s disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD. The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.